Our objective is to determine the extent to which various aspects of defense mechanisms and conditioned fear are relevant to features of particular forms of normal and abnormal anxiety in humans. We focus not only on the mechanisms underlying fear and anxiety (acquisition, extinction, generalization, expression), but also on how anxiety interferes with cognitive processing, leading to adaptive or maladaptive goal directed behaviors. Defining cognitive-attentional interactions that are central to anxiety may provide important links between brain dysfunction and clinical phenomenology. Experimental models: Our experimental models of anxiety are based on their presumed clinical relevance. We use virtual reality because it enables us to model phasic fear responses and sustained anxiety states (cue and context conditioning, respectively). In this type of experiment, fear and anxiety are assessed based on physiological responses. However, emotion (aversive states) can also be measured based on behavior (approach/avoidance). We obtained behavioral measures of fear and anxiety using a virtual reality analogue of the Morris water maze, a task in which subjects navigate to a hidden platform. The Morris water task presents important procedural differences compared to context conditioning;the shock is uncontrollable in context conditioning, whereas stressor duration is contingent on subjects behavior (i.e., reaching the hidden platform) in the Morris water maze. Recently, we have developed a procedure to study stimulus generalization, a learning mechanism by which conditioned fear generalizes to stimuli that resemble the original conditioned stimulus and may help maintain anxiety symptoms. Psychopharmacology: We have demonstrated the psychopharmacological validity of context conditioning as a model of anxiety. We recently showed that acute hydrocortisone treatment was anxiolytic in this experimental model. These results are significant because cortisol's effect on anxiety is believed to be mediated via its action on the consolidation and retrieval of emotional memories. Our results suggest a direct effect on the expression of anxiety. One possibility is that cortisol potentiates the effect of the stress hormone corticotrophin releasing factor in limbic system structures such as the bed nucleus of the stria terminalis. We are currently testing the effect of oxytocin and vasopressin on fear and anxiety. Oxytocin (OT) and vasopressin (AVP) are not only expected to have anxiolytic and anxiogenic properties, respectively, but, due to their distinct distribution in the amygdala they are also expected to affect different types of aversive states. More specifically, within the CeA, OT is concentrated in the lateral part, not the medial part, suggesting that it may influence preferentially BNST-mediated aversive states, which have been related to sustained anxiety in rodents. Meanwhile, AVP is concentrated in the medial part, not the lateral part, suggesting that it may influence preferentially medial central amygdala-mediated aversive states (i.e., phasic fear). Behavioral studies in patients: We have reported the first evidence of overgeneralization of conditioned fear in panic disorder. This proclivity to perturbed conditioned fear generalization may represent a potential pathogenic marker of panic disorder that explains the proliferation of cues that can trigger a panic attack (Lissek et al, 2010). Indeed, the proclivity towards overgeneralization may result in an increased likelihood of encountering panic reminder. Our current study investigates the interaction between anxiety evoked by anticipation of an aversive event and cognitive processing. In healthy subjects, anticipation of mild aversive stimuli does not interfere strongly with working memory. In fact, task performance acts as a buffer against anxiety. We predict that individuals with anxiety disorders are unable to mount such a buffer and that working memory performance will be impaired by aversive anticipation. Neuroimaging: The hippocampus is critically involved in learning and memory, but has also been broadly implicated in affective disorders. Using magnetoencephalography (MEG), we have studied spatial navigation in virtual reality as a model of hippocampal functioning. In one study, we demonstrated that patients with major depressive disorder show impaired spatial navigation and reduced recruitment of the right hippocampus in this task compared to healthy participants. These results fit with evidence of structural abnormalities of the hippocampus documented previously in depressed individuals. In a second study, we show that healthy participants, when threatened by unpredictable shocks, show increased activity in bilateral hippocampus and perform better at the task relative to normal safe conditions. These findings confirm that the hippocampus is an important structure for the interaction of anxiety and cognitive processes. An additional neuroimaging effort has been aimed at identifying the neural substrates of conditioned fear generalization of the kind we documented psychophysiologically in panic disorder (Lissek et al., 2010). Preliminary fMRI results in healthy participants (N=20) reveal graded decreases in brain activations associated with fear-excitation (i.e., anterior-insula and amygdala), and graded increases in areas associated with fear-inhibition (i.e., ventromedial-prefrontal-cortex/orbitofrontal-cortex) as the presented stimulus gradually differentiates from the CS+. Such findings indicate that putative neural substrates of fear-excitation and fear-inhibition closely track the fear-relevance of stimuli approximating a conditioned danger-cue, and the combined assessment of these excitation and inhibition areas may contribute importantly to the level of generalization displayed psychophysiologically and behaviorally. Further analyses will assess functional connectivity between regions instantiating the generalization gradient with special emphasis on the potential modulation of activity in these regions by the hippocampusa structure that may relay critical information about the CS+ similarity of presented stimuli to relevant brain structures, by way of schematic matching.